In this investigation the reaction properties of human hemoglobin (Hb) A and Hb S combined with pyridoxal, pyridoxal phosphate and related compounds will be examined, especially by means of measurements of the oxidation-reduction potential, Eh, of the ferriHb/ferroHb system. Previous investigations have shown that the oxidation of ferroHb resembles its oxygenation and other ligand equilibria in many respects, although the two are not identical in every detail, and the effects of variations in experimental conditions, such as pH, ionic strength, temperature, the concentrations of carbon dioxide, chloride and organic phosphates such as 2,3-diphosphoglycerate (DPG) have been well established, as well as the effects of chemical modification of the Hb. Many substances such as urea, cystamine, cyanate or pyridoxal, or procedures such as removal of carboxy-terminal amino acids, increase the affinity of Hb for oxygen (i.e., they lower the P50) and in parallel fashion they lower the oxidation-reduction potential (E50). This effect on oxygenation is of potential benefit in sickle cell disease although no clinically acceptable reaction or procedure has yet been found, which can be employed in an intact human being. Other substances such as inositol hexaphosphate or pyridoxal phosphate decrease the affinity of Hb for 02 (i.e., they raise the P50) and they likewise raise E50. Stroma-free Hb A, otherwise suitable for intravenous administration after trauma or during surgery has a lowered P50 as a result of removal of DPG, but treatment with pyridoxal phosphate, followed by reduction with sodium borohydride to form a stable covalent linkage, restores a normal P50. We have proposed that such stroma-free Hb A, combined with pyridoxal phosphate or other organic phosphate in stable linkage, will prove to be useful for therapeutic intervention in sickle cell disease, particularly in sickle cell disease. Compounds other than pyridoxal phosphate which can form stable combinations with hemoglobin include glucose-6-phosphate, norformyl pyridoxal phosphate and other dialdehyde phosphates.